In humans, infertility is said to be observed around 10% of couples. Therefore, there have been substantial needs for fertility treatment, and by now, it is a common practice. Among different procedures of fertility treatment, those in which sperm cell or eggs are directly handled are known as artificial insemination and in vitro fertilization, respectively. Artificial insemination is a technique to promote pregnancy by injecting sperm cells into the vagina at a position close to the cervix, or directly into the uterus or the oviducts, using an instrument such as catheter and the like, and it aims to increase the success rate of fertilization by avoiding obstacles that sperm cells might encounter until they could meet an egg. On the other hand, in vitro fertilization is a technique by which a patient is administered a fertility drug to induce generation of ova, which then are collected out of the body and mixed with sperm cells in a test tube (insemination) to have them got fertilized, and the fertilized eggs then are cultured and, on day 2 or 3 of culture in general, embryos at 4- or 8 cell stage are transferred into the uterine cavity in general, with a catheter. In order to make the implantation of the transferred embryos easier, administration of luteinizing hormone is usually conducted in order to condition the uterine endometrium.
A preimplantation embryo produces several factors during its development to signal its presence to the maternal organism. Interleukin-1 (IL-1), for example, is a primary factor which modulates cross talks between the embryo and the uterine endometrium of the maternal organism, and a complete IL-1 system is found in a human embryo at all the stages of its development (see Non-patent Document 1). With regard to human chorionic gonadotropin (HCG), another one of the factors released by an embryo, the transcription of its gene can be found to occur already in a 2-cell stage embryo (see Non-patent Document 2). It also is observed that several embryonic factors, including the above factors, involved in the cross talks are released out of the cell when it is cultured in vitro (in a test tube). Namely, several embryonic factors that modulate endometrial receptivity are detectable in the supernatant of embryo cultures (see Non-patent Documents 3-9). It also is known that, in vivo, an embryo developing in the oviduct induces differentiation of the uterine endometrium (see Non-patent Document 10). All these facts, taken together, indicate that the cross talks are brisk at the early stages of embryonic development, between the embryo and the uterine endometrium via the factors produced by the embryo. In fact, it has been shown that not only a preimplantation embryo in the uterine cavity, but also even an early embryo still remaining in the oviduct has the ability to modulate certain molecules in the uterine endometrium to place its implantation under its own control (see Non-patent Document 10).
In recent years, blastocyst transfer, a new technique of in vitro fertilization, has been proposed and practiced clinically as a means of improving the success rate of implantation in human fertility treatment (see Non-patent Documents 11-13). In this technique, embryos produced by in vitro fertilization as described above are cultured for 5 to 6 days to let them develop into blastocysts and then injected into the uterine cavity. Employing the technique of blastocyst transfer, higher implantation rates result compared with the transfer of embryos at earlier stages, for the former allows physiological synchronization of the uterine endometrium with the developmental stage of the embryos, as well as relatively easier selection of embryos with higher ability for implantation owing to a longer in vitro culture (see Non-patent Documents 14 and 15). That the number of days required for implantation to occur after blastocyst transfer is as short as 1 day, in contrast with the 4-5 days required with 2-3 day-cultured embryos, reduces the risk of washout of embryos out of the uterus, and is therefore beneficial to implantation. Even so, however, the success rate of pregnancy by human blastocyst transfer actually remains at a low level of about 36.4%. Unsuccessful implantation after blastocyst transfer is thought to be due, e.g., to failure of the blastocyst to escape from the zona pellucida or to arrested development of the transplanted blastocyst in the uterine cavity. Thus, as there is still a majority of cases where blastocyst transfer fails to achieve pregnancy, further means is needed to increase the success rate of achieving pregnancy.    [Non-patent Document 1] De los Santos M J, Anderson D J, Racowsky C, Simon C, and Hill J A (1998) Biol Reprod. 59, 1419-1424    [Non-patent Document 2] Jurisicova A, Antenos M, Kapasi K, Meriano J, and Casper R F (1999) Hum Reprod. 14, 1852-1858    [Non-patent Document 3] Tazuke S I, and Giudice L C, (1996) Semin Reprod Endocrinol. 14, 231-245    [Non-patent Document 4] Simon C, Gimeno M J, Mercader A, O'Connor J E, Remohi J, Polan M L, and Pellicer A (1997) J Clin Endocrinol Metab. 82, 2607-2616    [Non-patent Document 5] Giudice L C (1995) Semin Reprod Endocrinol. 13, 93-101    [Non-patent Document 6] Sheth K V, Roca G L, al-Sedairy S T, Parhar R S, Hamilton C J, and al-Abdul Jabbar F (1991) Fertil Steril. 55, 952-957    [Non-patent Document 7] Baranao R I, Piazza A, Rumi L S, and Polak de Fried E (1997) Am J Reprod Immunol. 37, 191-194    [Non-patent Document 8] Licht P, Russu V, and Wildt L (2001) Semin Reprod Med. 19, 37-47    [Non-patent Document 1] Perrier d'Hauterive S, Charlet-Renard C, Berndt S, Dubois M, Munaut C, Goffin F, et. al. (2004) Hum Reprod. 19, 2633-2643    [Non-patent Document 10] Wakuda K, Takakura K, Nakanishi K, Kita N, Shi H, Hirose M, and Noda Y (1999) J Reprod Fertil. 115, 315-324    [Non-patent Document 11] Gardner D K, Schoolcraft W B, Wagley L, Schlenker T, Stevens J, and Hesla J A (1998) Hum Reprod. 13, 3434-3440    [Non-patent Document 12] Scholtes M C, and Zeilmaker G H (1998) Fertil Steril. 69, 78-83    [Non-patent Document 13] Milki A A, Fisch J D, and Behr B (1999) Fertil Steril. 72, 225-228    [Non-patent Document 14] Gardner D K, Vella P, Lane M, Wagley L, Schlenker T, and Schoolcraft W B (1998) Fertil Steril. 69, 84-88    [Non-patent Document 15] Edwards R G, and Beard H K (1999) Hum Reprod. 14, 1-4